The overall goal of this project is to understand the role of poly(ADP-ribose) in the pathogenesis and pathology of neuronal injury following excitotoxicity and ischemia-reperfusion injury. The Program represents a multi-disciplinary, mechanistic approach involving interactive, productive investigators with complimentary areas of expertise who have a long-term commitment to studies of neuronal injury. This Program will integrate the activities of various disciplines such that the interrelationships will result in a greater scientific contribution than could be achieved if each project were pursued individually. The Program has two themes: first, to understand the cell biology and biochemistry of poly(ADP-ribose) as a signaling molecule which results in neuronal damage. Wild-type and mutant mice will be used to the actions of poly(ADP-ribose) and to determine the cellular targets of poly(ADP-ribose) activity that trigger neuronal cell death. Second, the actions of apoptosis inducing factor and endonuclease G as downstream mediators of PAR dependent cell death, will be explored using molecular biologic, cell biologic and pathologic experiments. State of the art molecular, cellular, neuropathological, physiological and proteomic approaches are used throughout the Program. The Program has several important strengths. The investigators have a history of interactive studies of neuronal injury and mechanisms to limit injury in the nervous system. The investigators are leaders in the field of neuronal injury and ischemia. Sophisticated experimental approaches are used to gain insight into this novel mediator of neuronal death. We believe that our multi-disciplinary approach has the capacity to produce unique information conceming the mechanism of neuronal injury mediated by poly(ADP-ribose) and translocation of apoptosis inducing factor to hopefully determine new therapeutic opportunities to capitalize on the observation of profound neuroprotection observed in the poly(ADP-ribose) polymerase knockout mice. The Program consists of three projects and two cores: 1) Apoptosis Inducing Factor in Neuronal Injury, 2) Poly(ADP-ribose) Signaling in Glutamate Excitotoxicity, 3) Molecular Mechanisms of PARP-Dependent Cell Death in Stroke, A) Administrative Core, B) Gene Expression Core.